Primary hypertension is the most prevalent type of hypertension, affecting 90-95% of hypertensive patients. However, the underlying etiology of primary hypertension remains poorly understood. The sympathetic drive emanating from the brain is increased in animal models of hypertension and in patients with primary hypertension. The paraventricular nucleus (PVN) of the hypothalamus is an important site in the central nervous system for increased sympathetic outflow through its projections to sympathetically related sites in the brainstem and spinal cord in multiple forms of hypertension. Increased excitability of presympathetic neurons in the PVN are critically involved in the development of hypertension. In this application, we propose to determine the upstream signaling mechanisms responsible for the long-lasting neuronal and synaptic plasticity in the PVN in hypertension. Our preliminary data suggest that Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the PVN is upregulated and contributes to the maintenance of increased sympathetic drive in hypertension. We will use animal models of hypertension to test our overall hypothesis that increased CaMKII activity in the PVN contributes to elevated sympathetic vasomotor tone by augmenting N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory input in hypertension and that reduced calcineurin activity in the PVN in hypertension potentiates CaMKII activity and NMDAR-mediated excitatory input. The important roles of CaMKII and calcineurin in the PVN in synaptic integration and neuronal plasticity associated with development of hypertension have not been previously recognized. Our proposed studies are expected to unravel a cascade of molecular events responsible for the sustained increase in sympathetic vasomotor tone in hypertension. This new information should have a major impact on our understanding of the fundamental mechanisms underlying the development of neurogenic hypertension and on the design of new treatments for resistant and neurogenic hypertension.